Synthesis of hydroxyethyltetrazolethiol and etherified intermediates therefor

ABSTRACT

By heating an N-(2-hydroxyethyl)dithiocarbamate ester protected at its hydroxy group as an ether in the presence of an azide, the corresponding 1-(protected hydroxyethyl)-1H-tetrazole-5-thiol is obtained, and then, if required, deprotecting the etheric protection to give an industrially useful chemical, 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol.

1. INTRODUCTION

This invention relates to an improved synthesis of1-hydroxyethyl-1H-tetrazole-5-thiol or its mercaptide salt (III) whichcomprises heating an N-hydroxyethyldithiocarbamate ester protected atits hydroxy in the form of an ether (I) in the presence of an azide inan inert solvent and then deprotecting the produced corresponding1-(protected hydroxyethyl)-1H-tetrazole-5-thiol or its mercaptide salt(II) according to the following scheme. ##STR1## wherein

R is an ether forming group,

R¹ is an ester forming group and

R² is hydrogen or a salt forming atom or group.

2. BACKGROUND OF INVENTION

The objective compound of this invention (III) is already known e.g. bythe specification of Japanese Patent Applications Kokai Nos. 51-68,568and 52-33,692. However, when the examples of said patent literatureswere traced by the present invention, the yield was found to be about 20to 30%. They then sought several measures for improving the yield tofind that when the hydroxyl group of the hydroxyethyldithiocarbamate isprotected in an ether form, the yield was raised up to 90%. Based onthis discovery, this invention was established.

3. STARTING MATERIALS

The starting material of the old process,N-(2-hydroxyethyl)-dithiocarbamic acid ester, is a known compound.However, the compound protected at its hydroxy as an ether (I) is a newcompound. This form of protection protects the hydroxyethyl compoundsfrom the basicity and reactivity of the azide in the reaction medium,and among them, more preferable protecting groups are those removableunder a mild condition.

Representative ether forming groups suitable for the object of thisinvention and represented by R include linear, branched, cyclic orpartly cyclic alkyl, aralkyl, aryl, heterocyclic, organosilyl andorganostannyl groups. All of these can be unsaturated and/or substitutedby a group inert to this reaction, e.g., C₁ to C₃ -alkyl, alkoxy, aryl,halogen or nitro, and/or interrupted by a hetero atom selected fromoxygen, nitrogen and sulfur in its nucleus, and containing 1 to 20carbon atoms.

More preferable groups for R include an 2-oxaalicyclic group or alkyloptionally substituted at the 1 position with alkoxy or aryl. Furtherpreferable groups for R are C₄ to C₇ -tertiary alkyl, 1-C₁ to C₆-alkoxy-C₁ to C₆ -alkyl, C₄ to C₆ -2-oxacycloalkyl or triarylmethyl, andthe most preferable R is a group selected from t-butyl, 1-ethoxyethyl,1-isobutoxyethyl, 1-methoxy-1-methylethyl, tetrahydropyran-2-yl andtrityl.

Preferable ester forming groups for R¹ are C₁ to C₆ -(more preferably,C₁ to C₃)-alkyl.

The hydroxy group of the N-(2-hydroxyethyl)dithiocarbamate ester (II)can be protected in a conventional manner in the art for the specificprotective group to be introduced, e.g., the addition to an olefin orcondensation with a halide.

4. TETRAZOLE RING FORMATION

The tetrazole ring closure is carried out by heating thehydroxy-protected N-(2-hydroxyethyl)dithiocarbamic acid ester (I) in aninert solvent in the presence of an azide, e.g., an alkali metal oralkaline earth metal azide. ##STR2## wherein R, R¹ and R² are as definedabove. The inert solvent can be an aqueous solvent, e.g., C₁ to C₄-alkanol, C₄ to C₆ -straight or cyclic ether or another industrialwater-miscible solvent or mixture of these. The reaction is usuallycomplete at a temperature between 30° C. and 150° C. in 0.5 to 10 hours.

The produced 1-(protected hydroxyethyl)-1H-tetrazole-5-thiol or itsmercaptide salt (II) is a novel compound and can be isolated andpurified in a manner conventional in the art, e.g., concentration,partition, extraction, washing, adsorption, elution, crystallizationand/or drying. Preferable mercaptides for R² are alkali metal andalkaline earth metal atoms and are usually formed by a conventionalmixing with a base.

5. DEPROTECTION

The deprotection of this intermediate (II) can be carried out in amanner conventional in the art for the removal of the protection groupe.g., by the hydrolysis or elimination with an acid, e.g., Lewis acid,mineral acid, carboxylic acid, sulfonic acid, or for some groups,hydrogenolysis in the presence of a palladium or nickel catalyst, togive 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol or its salt (III) accordingto the following scheme ##STR3## wherein R and R² are as defined above.

The deprotection can be done in an industrial inert solvent, preferablya polar solvent for the proton acid deprotection or a nonpolar solventfor the Lewis acid deprotection. Specific examples of these includewater, a C₁ to C₆ -alkanol, C₃ to C₆ -straight or cyclic ether, C₃ to C₆-alkanone, C₁ to C₆ -haloalkane or C₆ to C₈ -aromatic hydrocarbonsolvent or a mixture of these.

The deprotection is preferably carried out in an aqueous solvent at a pHbetween 0 to 4 with a mineral acid, carboxylic acid or sulfonic acid, orin an anhydrous solvent with a Lewis acid, both at a temperature between-20° C. and 150° C. for a time between 5 minutes and 10 hours.

For 1 mole of the starting material, 0.4 to 10 molar equivalents of thereagent is usually used. The reaction can be carried out, if required,under an inert gas, e.g., nitrogen.

The reaction conditions given above for both of the tetrazole ringformation and deprotection show some preferable ranges, but are not tobe taken as the critical ones.

6. TYPICAL REACTIONS

In a typical run, the dithiocarbamic acid alkyl ester (I) wherein R istertiary butyl, 1-C₁ to C₄ -alkoxy-C₁ to C₃ -alkyl, tetrahydropyran-2-ylor triphenylmethyl and R¹ is C₁ to C₃ -alkyl, is heated in the presenceof 1 to 3 molar equivalents of an alkali metal azide in a mixture of 1to 40 parts by weight of C₁ to C₆ -alkanol or C₄ to C₆ -dioxacycloalkaneand 1 to 10 parts by weight of water at a temperature between 40° C. and150° C. for a time between 35 and 330 minutes to form the alkali metalmercaptide salt of the compound (II) where R² is alkali metal. By aconventional work up, this affords the free thiol (II) where R² ishydrogen.

A typical deprotection is carried out by keeping 1-(protectedhydroxyethyl)-1H-tetrazole-5-thiol (II) where R is tertiary butyl, 1-C₁to C₄ -alkoxy-C₁ to C₃ -alkyl, tetrahydropyran-2-yl or triphenylmethyland R² is hydrogen or alkali metal, at a pH between 0.5 to 4 in amixture of 0 to 30 parts by weight of C₁ to C₆ -alkanol, C₃ to C₆-alkanone or C₄ to C₆ -dioxacycloalkane and 0 to 33 parts by weight ofwater at a temperature between 0° C. and 40° C. for a time between 5 and330 minutes to form the free thiol compound (III) where R² is hydrogen.

Alternatively, the same starting material (II) is dissolved in a mixtureof 0 to 20 parts by weight of C₁ to C₆ -halohydrocarbon, 0.5 to 5 partsby weight of trifluoroacetic acid or 0.5 to 5 molar equivalents ofaluminum or titanium chloride and 1 to 5 parts by weight of anisole,kept at a temperature between -10° C. and 40° C. for a time between 5minutes and 3 hours, and then concentrated to remove the volatilematerial and washed to remove the reagent and by-products to obtain thethiol compound (III) where R² is hydrogen.

7. USE OF THE PRODUCTS

The products thus prepared can be used as an elasticizer or startingmaterial for preparing useful pharmaceuticals, e.g., cephalosporins, oragricultural chemicals.

8. NOVEL COMPOUNDS

The starting materials (I) and intermediates (II) are novel compoundsrepresented by the following formula ##STR4## wherein R, R¹ and R² areas defined above.

A preferable R group is a 2-oxaalicyclic group or alkyl group optionallysubstituted at the 1 position with alkoxy or aryl; and a more preferableR group is C₄ to C₇ -tertiary alkyl, triarylmethyl, 1-C₁ to C₆-alkoxy-C₁ to C₆ -alkyl or C₄ to C₇ -oxacycloalkan-2-yl. Some of thespecific groups for R are t-butyl, 1-ethoxyethyl, 1-isobutoxyethyl,1-methoxy-1-methylethyl, tetrahydropyran-2-yl and trityl. Preferable R¹groups are methyl, ethyl or propyl. Preferable R² groups are alkalimetal, e.g., lithium, sodium or potassium.

9. PREPARATION OF THE STARTING MATERIALS (I)

(Non-protected dithiocarbamate)

To a solution of ethanolamine (30.54 g) in a mixture of ethanol (370 ml)and water (30 ml) are added triethylamine (60.6 g) and carbon disulfide(45 g) at 15° C. After stirring for 1 hour, methyl iodide (80 g) isadded thereto at 15° C. After 30 minutes' stirring, the reaction mixtureis concentrated under reduced pressure, diluted with water (350 ml) andhexane, shaken and left to stand for a while to separate a water layer.The aqueous layer is acidified with phosphoric acid (1.5 ml), andextracted with ethyl acetate under salt-out condition. The extract isevaporated to remove the solvent to giveN-(2-hydroxyethyl)dithiocarbamic acid methyl ester (81.7 g).

NMR(CDCl₃) δ: 2.63(s, 3H), 2.73-3.08(m, 1H), 3.60-4.17(brs, 4H),7.50-8.17(m, 1H).

(Protected dithiocarbamates)

(1) To a solution of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester(7.5 g) in pyridine (40 ml) is added triphenylmethyl chloride (15 g),and the mixture is left to stand overnight at room temperature. Thereaction mixture is poured into water and extracted with ethyl acetate.The extract is washed with diluted hydrochloric acid and water, driedand concentrated to remove the solvent. The residue is crystallized froma mixture of dichloromethane and ether to giveN-(2-triphenylmethoxyethyl)dithiocarbamic acid methyl ester (14.73 g).

(2) In a sealed glass tube is placed a solution ofN-(2-hydroxyethyl)dithiocarbamic acid methyl ester (4.3 g), isobutene(30 ml) and concentrated sulfuric acid (0.1 ml) in dichloromethane (20ml) prepared at -50° C. to -60° C. The mixture is warmed slowly to roomtemperature and then left to stand for 17 hours. The reaction mixture ispoured into aqueous 0.5% sodium hydroxide and extracted withdichloromethane. The extract is washed with water, dried andconcentrated to give N-(2-t-butoxyethyl)dithiocarbamic acid methylester.

(3) To a solution of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester(81.7 g) in dichloromethane (300 ml) are added dihydropyran (54 g) andtoluene-p-sulfonic acid monohydrate (1.0 g), and the mixture is stirredfor 1 hour. The reaction mixture is poured in aqueous sodium hydrogencarbonate, shaken and the resulting organic layer is separated. Thelayer is concentrated under reduced pressure to giveN-[2-(2-tetrahydropyranyl)oxyethyl]dithiocarbamic acid methyl ester (129g).

(4) To an ice cold and stirred mixture ofN-(2-hydroxyethyl)dithiocarbamic acid methyl ester (1.513 g) andethoxyethylene (1.92 ml) is added toluene-p-sulfonic acid monohydrate(9.5 mg). After stirring for 30 minutes at room temperature, thehomogeneous solution is mixed with triethylamine (8 μl) and concentratedunder reduced pressure to yieldN-[2-(1-ethoxyethoxy)ethyl]dithiocarbamic acid methyl ester (2.4 g).

(5) To a mixture of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester(1.513 g) and isobutoxyethylene (2.59 ml) is added toluene-p-sulfonicacid monohydrate (9.5 mg). After stirring for 30 minutes, triethylamine(8 μl) is added to the mixture, and the resulting solution isconcentrated under reduced pressure to giveN-[2-(1-isobutoxyethyl)ethyl]dithiocarbamic acid methyl ester (3.2 g).Yield: 95%.

(6) To a mixture of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester(1.513 g) and 2-methoxypropene (1.92 ml) is added toluene-p-sulfonicacid monohydrate (9.5 mg) at 10° C. After stirring for 1 hour, a traceamount of triethylamine is added and concentrated under reduced pressureto give N-[2-(2-methoxyisopropoxy)ethyl]dithiocarbamic acid methyl ester(2.78 g). Yield: 80%.

10. EXAMPLES

The following examples are given to illustrate embodiments of thisinvention.

In the following examples, the concentration is usually carried outunder reduced pressure until the volatile solvent used is removed; andthe drying is done with sodium sulfate or magnesium sulfate for theconvenience of the laboratory use. The J-values in the NMR data show thecoupling constants in Hz-values with an apparatus of 60 Mc.

EXAMPLE 1 (Tetrazole ring formation)

To a solution of N-(2-protected hydroxyethyl)dithiocarbamic acid methylester in a solvent is added a solution of sodium azide in water. Afterheating for the given time, the mixture is concentrated to remove thesolvent, dissolved in water, washed with ethyl acetate, acidified withphosphoric acid and extracted with ethyl acetate. The extract is washedwith water, dried and concentrated to give the corresponding1-(2-protected hydroxyethyl)-1H-tetrazole-5-thiol.

The reaction conditions are given on Table I-1 and the physicalconstants of the products are given in Table II-2.

EXAMPLE 2 (Deprotection)

(1) A solution of 1-(2-protected hydroxyethyl)-1H-tetrazole-5-thiol in asolvent is acidified with an acid to the given pH and the mixture iskept at the given temperature for the given time. The reaction mixtureis concentrated under reduced pressure. The obtained residue isextracted with ether, dried and concentrated. The residue iscrystallized from a mixture of ethyl acetate and hexane to give1-(2-hydroxyethyl)-1H-tetrazole-5-thiol. mp. 135°-137° C.

The reaction conditions are given in Table I-2.

EXAMPLE 3 (Deprotection)

To a solution of aluminum chloride (0.2 g) in anisole (1 ml) cooled at0° C. is added a solution of 1-(2-t-butoxyethyl)-1H-tetrazole-5-thiol(0.202 g) in dichloromethane (2 ml), and the mixture is stirred at roomtemperature for 3 hours. The reaction mixture is poured into a mixtureof 3N-hydrochloric acid (10 ml) and ethyl acetate (20 ml), shaken andthe resulting organic layer is taken up. The layer is extracted withaqueous 5% sodium hydroxide. The extract is acidified with hydrochloricacid and extracted again with ethyl acetate. The extract is concentratedunder reduced pressure to give 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol.mp. 135°-136° C.

EXAMPLE 4 (Sodium salt)

A solution of 1-[2-(tetrahydropyran-2-yl)oxyethyl]-1H-tetrazole-5-thiol(23 g) in water (120 ml) containing sodium hydrogen carbonate (8.4 g) isconcentrated under reduced pressure. The residue is crystallized from amixture of ether and hexane to give1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-tetrazole-5-thiol sodium salt(23.5 g). mp. 177°-180° C.

                                      TABLE I-1                                   __________________________________________________________________________    Reaction conditions of the tetrazole formation                                 ##STR5##                                                                                  NaN.sub.3                                                                          solvent                                                                            H.sub.2 O                                                                          Time                                                                              Temperature                                   No. R        (mole)                                                                             (amount)                                                                           (amt)                                                                              (min.)                                                                            (°C.)                                  __________________________________________________________________________    1   t-C.sub.4 H.sub.9                                                                      1.2  C.sub.2 H.sub.5 OH                                                                 3.1  120 refl.                                                           10                                                          2   t-C.sub.4 H.sub.9                                                                      3.0  dioxane                                                                            10    60 80                                                              40                                                            3                                                                                ##STR6##                                                                              1.3  C.sub.2 H.sub.5 OH 6.7                                                             3.3   80 refl.                                           4                                                                                ##STR7##                                                                              1.1  CH.sub.3 OH 1.2                                                                    2.3  330 40                                              5                                                                                ##STR8##                                                                              1.3  C.sub. 2 H.sub.5 OH 6.3                                                            3.2   80 refl.                                           6 CH.sub.3 OC(CH.sub.3).sub.2                                                            1.0  C.sub.2 H.sub.5 OH                                                                 4.0   35 refl.                                                           7.8                                                           7                                                                                ##STR9##                                                                              1.2  C.sub.2 H.sub.5 OH 2.6                                                             1.7  150 refl.                                           8 (C.sub.6 H.sub.5).sub.3 C                                                              1.2  C.sub.2 H.sub.5 OH                                                                 3.7  120 refl.                                                           10.1                                                        __________________________________________________________________________     Note:                                                                         (a) The amount of the solvent and water is expressed by the weight ratio      to the dithiocarbamate starting material.                                     (b) refl. shows heating under reflux.                                    

                                      TABLE I-2                                   __________________________________________________________________________    Deprotections of the protected hydroxy.                                        ##STR10##                                                                                  Solvent Water   Temp.                                                                             Time                                        No. R         (amt.)  (amt.)                                                                            pH  (°C.)                                                                      (min.)                                      __________________________________________________________________________         ##STR11##                                                                              CH.sub.3 COCH.sub.3  10                                                               0.5 2   0   50                                             2                                                                               ##STR12##                                                                              C.sub.2 H.sub.5 OH 30                                                                 20  1   0    5                                            3                                                                                ##STR13##                                                                              CH.sub.3 COCH.sub.3  7                                                                0.5 2   0   50                                            4 CH.sub.3 OC(CH.sub.3).sub.2                                                             --      5   2   rt  10                                            5                                                                                ##STR14##                                                                              CH.sub.3 COCH.sub.3  4.5                                                              4   2   rt  120                                           6                                                                                ##STR15##                                                                              dioxane 2                                                                             1   4   40  330                                           7 (C.sub.6 H.sub.5).sub.3 C                                                               CH.sub.3 OH                                                                           33  0.5 rt  300                                                               3                                                       __________________________________________________________________________     Note:                                                                         1. The amount of the solvent and water is expressed by the weight ratio t     the protected hydroxyethyltetrazolethiol.                                     2. rt shows room temperature.                                            

                                      TABLE II-1                                  __________________________________________________________________________    Physical constants of the starting dithiocarbamic                             acid methyl esters, ROCH.sub.2 CH.sub.2 NHCSSCH.sub.3 (I)                     No.                                                                              R        IR: ν .sub.max.sup.CHCl.sbsp.3 cm.sup.-1                                            NMR: δ .sub.ppm.sup.CDCl.sbsp.3                    __________________________________________________________________________    1  t-C.sub.4 H.sub.9                                                                      --       1.2(s,9H), 2.63(s,3H), 3.55                                                   (t,J = 4.5Hz,2H), 3.73-4.03                                                   (m,2H).                                                    2                                                                               ##STR16##                                                                             3370, 3245.                                                                            1.22(t,J = 7Hz,3H), 1.35(d, J = 5Hz,3H), 1.57(s,1H),                          3.4-4.1 (m,4H), 4.69(q,J = 5Hz,1H).                        3                                                                               ##STR17##                                                                             3370, 3235.                                                                            0.91(d,J = 7Hz,6H), 1.30(d,J = 5Hz, 3H), 1.52(s,1H),                          1.6(m,1H), 2.64(s,3H), 3.1-4.1(m,6H), 4.68(q,J =                              5Hz,1H).                                                   4                                                                              CH.sub.3 OC(CH.sub.3).sub.2                                                            3380, 3250, 1601.                                                                      1.33(s,6H), 2.63(s,3H), 3.19                                                  (s,3H), 3.63(t,J = 4Hz,2H),                                                   3.89(t,J = 4Hz,2H).                                        5                                                                               ##STR18##                                                                             3360.    1.33-2.00(m,6H), 2.63(s,3H), 3.47-4.17(s,6H),                                 4.33-4.67 (m,1H), 7.50-8.33(m,1H).                         6                                                                              (C.sub.6 H.sub.5).sub.3 C                                                              3360.    2.60(s,3H), 3.35(t,J = 5Hz,2H),                                               3.60-4.07(m,2H), 7.07-7.63                                                    (m,16H).                                                 __________________________________________________________________________

                                      TABLE II-2                                  __________________________________________________________________________    Physical constants of the 1-protected hydroxyethyltetrazole-5-thiols.          ##STR19##                                                                    No.                                                                              R        IR: ν .sub.max.sup.CHCl.sbsp.3 cm.sup.-1                                            NMR: δ .sub.ppm.sup.CDCl.sbsp.3                    __________________________________________________________________________    1  t-C.sub.4 H.sub.9                                                                      --       1.3(s,9H), 3.87(t,J = 5.25Hz,2H),                                             4.47(t,J = 5.25Hz,2H), 11.87(s,1H).                        2                                                                               ##STR20##                                                                             3397.    1.07(t,J = 7Hz,3H), 1.17(d,J = 6Hz, 3H), 3.40(q,J =                           7Hz,2H), 3.98 (t,J = 5Hz,2H), 4.43(t,J = 5Hz,2H),                             4.69(q,J = 6Hz,1H), 7.5(brs,1H).                           3                                                                               ##STR21##                                                                             3415.    0.90(d,J = 6Hz,6H), 1.28(d,J = 6Hz, 3H), 1.82(m,1H),                          3.20(m,2H), 4.00(t,J = 5Hz,2H), 4.52(t,J = 5Hz,2H),                           4.75(q,J = 6Hz,1H), 10.0(brs, 1H).                         4                                                                              CH.sub.3 OC(CH.sub.3).sub. 2                                                           --       --                                                         5                                                                               ##STR22##                                                                             --       1.33-1.87(m,6H), 3.40-4.87(m, 7H),                                            12.57-13.16(m,1H).                                         6                                                                              (C.sub.6 H.sub.5).sub.3 C                                                              --       3.50(t,J = 5Hz,2H), 4.45(t,J = 5Hz,                                           2H), 6.97-7.43(brs,15H)(CD.sub.3 COCD.sub.3).            __________________________________________________________________________

What we claim is:
 1. A process for preparing optionally protected1-hydroxyethyl-1H-tetrazole-5-thiol or the mercaptide salt thereof whichcomprises the steps of heating an etherifiedN-hydroxyethyldithiocarbamate ester (I) in the presence of an azide inan inert solvent to give the corresponding etherified1-(hydroxyethyl)-1H-tetrazole-5-thiol or the mercaptide salt thereof(II) and then, if required, removing the ether-forming group to give thefree alcohol compound (III), the compounds I, (II) and (III) having thefollowing formulae: ##STR23## wherein R is an ether forming groupselected from the group consisting of tertiary alkyl, triarylmethyl,1-(C₁ to C₆ -alkoxy)-C₁ to C₆ -alkyl and C₄ to C₆ -2-oxacycloalk-1-yl,R¹ is an ester forming group and R² is hydrogen or an alkali metal oralkaline earth metal salt forming group.
 2. A process as claimed inclaim 1 wherein R is C₄ to C₇ -tertiary alkyl.
 3. A process as claimedin claim 1 wherein R is triarylmethyl.
 4. A process as claimed in claim1 wherein R is a group selected from t-butyl, 1-ethoxyethyl,1-isobutoxyethyl, 1-methoxy-1-methylethyl, tetrahydropyran-2-yl andtrityl.
 5. A process as claimed in claim 1 wherein R¹ is C₁ to C₆-alkyl.
 6. A process claimed in claim 1 wherein the azide is an alkalimetal or alkaline earth metal azide.
 7. A process as claimed in claim 1wherein the mercaptide salt R² is an alkali metal or alkaline earthmetal salt.
 8. A process as claimed in claim 1 wherein the inert solventis an aqueous solvent.
 9. A process as claimed in claim 1 wherein theheating is conducted to keep the medium at a temperature between 30° C.and 150° C. for a time between 0.5 and 10 hours.
 10. A process asclaimed in claim 1 wherein the removal of the ether-forming group iscarried out in an aqueous medium at a pH between 0 to 4 with a mineralacid, carboxylic acid or sulfonic acid.
 11. A process as claimed inclaim 1 wherein the removal of the ether-forming group is carried out inan anhydrous medium with a Lewis acid.
 12. A process as claimed in claim1 wherein the removal of the ether-forming group is carried out at atemperature between -20° C. and 150° C. for a time between 5 minutes and10 hours.
 13. A process as claimed in claim 1 wherein R is tertiarybutyl, 1-(C₁ to C₄ -alkoxy)-C₁ to C₃ -alkyl, tetrahydropyran-2-yl ortriphenylmethyl and R¹ is C₁ to C₃ -alkyl, which comprises heating thecorresponding dithiocarbamate ester (I) in the presence of 1 to 3 molarequivalents of the alkali metal azide in a mixture of 1 to 40 parts byweight of a C₁ to C₆ -alkanol or C₄ to C₆ -dioxacycloalkane and 0 to 10parts by weight of water at a temperature between 40° C. and 150° C. fora time between 35 and 330 minutes.
 14. A process as claimed in claim 1wherein R is tertiary butyl, 1-C₁ to C₄ -alkoxy-C₁ to C₃ -alkyl,tetrahydropyran-2-yl or triarylmethyl and R¹ is C₁ to C₃ -alkyl, whichcomprises maintaining the 1-(etherifiedhydroxyethyl)-1H-tetrazole-5-thiol or its alkali metal salt at a pHbetween 0.5 and 4 in a mixture of 0 to 30 parts by weight of C₁ to C₆-alkanol, C₃ to C₆ -alkanone or C₄ to C₆ -dioxacycloalkane and 1 to 33parts by weight of water at a temperature between 0° C. and 40° C. for atime between 5 and 330 minutes.
 15. A process as claimed in claim 1wherein R is tertiary butyl, 1-C₁ to C₄ -alkoxy-C₁ to C₃ -alkyl,tetrahydropyran-2-yl or triarylmethyl and R¹ is C₁ to C₃ -alkyl, whichcomprises maintaining the 1-(etherifiedhydroxyethyl)-1H-tetrazole-5-thiol at a temperature between -10° C. and40° C. in a mixture of 0 to 20 parts by weight of C₁ to C₆-halohydrocarbon, 0.5 to 5 parts by weight of trifluoroacetic acid or0.5 to 5 molar equivalents of aluminum or titanium chloride and 1 to 5parts by weight of anisole for a time between 5 minutes and 3 hours. 16.A process as claimed in claim 1, wherein R¹ is C₁ to C₃ -alkyl.
 17. AnN-(etherified hydroxyethyl)dithiocarbamic acid alkyl ester or1-(etherified hydroxyethyl)-1H-tetrazole-5-thiol compound represented bythe following formula ##STR24## wherein R is an ether forming group, R¹is alkyl andR² is hydrogen or alkali metal.
 18. A compound as claimed inclaim 17 wherein R is C₄ to C₇ -tertiary alkyl, 1-(C₁ to C₆ -alkoxy)-C₁to C₆ -alkyl, C₄ to C₆ -oxacycloalkan-2-yl or triarylmethyl, R¹ ismethyl, ethyl, propyl or isopropyl, and R² is lithium, sodium orpotassium.